(i) Field of the Invention:
The present invention relates to antibodies against periostin isoforms having anti-cell adhesive properties, especially anti-periostin antibodies having the ability to neutralize anti-cell adhesive properties. More specifically, it relates to anti-periostin antibodies specifically recognizing a site responsible for anti-cell adhesion of periostin having anti-cell adhesive properties specifically expressed in interstitial tissue during tissue restructuring such as cardiac hypertrophy, which are useful for prevention or treatment of periostin-related diseases, such as heart failure, or are useful for diagnosis of these diseases.
The present invention also relates to a pharmaceutical composition for cancer treatment, which comprises an antibody against a peptide encoded by the Exon-17 region of periostin. More specifically, the present invention relates to a pharmaceutical composition for cancer treatment, which comprises an anti-periostin antibody recognizing a splice variant of periostin having anti-cell adhesive properties specifically expressed in interstitial tissue during tissue restructuring such as cancer tissues, or a method and reagent for cancer diagnosis using the above anti-periostin antibody.
(ii) Description of the Related Art:
Chronic heart failure is a condition in which the heart cannot pump enough blood to various organs due to decreased myocardial contractility. Conventionally, it has been treated with cardiotonic drugs that increase myocardial contractility such as digitalis drugs. However, these drugs have been shown to impair vital prognosis during long-term administration, due to excessive consumption of myocardial energy. Thus, recently prevailing therapies are those using diuretics, β-blockers or angiotensin inhibitors that reduce excessive workload on the heart by the sympathetic nervous system or renin-angiotensin-aldosterone system activated in heart failure condition. However, patients with heart failure have limited activities in their daily life and cannot maintain their quality of life because they are prohibited from hard exercise or the like. Moreover, the vital prognosis of patients with heart failure cannot be fully ensured. It is therefore desirable to develop a new drug effective for treating heart failure, which enables an improvement in the quality of life and an improvement in long-term vital prognosis.
In recent years, the healing rate of cancer has been rising steadily with advances in cancer therapy. In particular, the improved success rate of primary carcinoma removal by surgical operation, radiation therapy or chemotherapy contributes to the advance of cancer therapy. However, on a worldwide basis, the cancer mortality rate continues to increase for reasons such as aging population, and cancer remains the primary cause of death. This is because not a few patients will die of cancer metastasis even when primary carcinoma removal is completely achieved, and there is a limit to surgical operation, radiation therapy or chemotherapy for completely blocking cancer metastasis, so that the distant metastasis of cancer is still directly or indirectly related to the cause of cancer death. Cancer metastasis is mediated by processes such as invasion of cancer cells released from their primary tumor into blood vessels or lymph vessels, selective migration of cancer cells to metastatic organs, invasion of cancer cells from blood vessels into metastatic organs, growth of cancer cells supported by the microenvironment where metastasis occurred, and angiogenesis-associated growth of tumors whose diameter exceeds several millimeters (Folkman J. Semin. Cancer Biol, 3, 65-71, (1992), Hanahan D. et al. Cell, 86, 353-364 (1996)). Among these complex processes for metastasis establishment, invasion and metastasis induced by the enhanced motility of cancer cells are very important stages (Liotta L A. et al. Cell, 64, 327-336 (1991)). Until now, it has been reported that highly metastatic cancer cells produce an autocrine motility factor by themselves to enhance their own motion (Liotta L A. et al. Proc. Natl. Acad. Sci., 83, 3302-3306 (1986)). Inhibitory substances against this malignant factor are expected as metastasis inhibitors, but no specific inhibitor has been found at present.
On the other hand, periostin is an extracellular matrix protein and consists of a polypeptide having a molecular weight of about 90000. Each polypeptide chain has a signal sequence, a cysteine-rich domain, a fourfold repeated domain, and a C-terminal domain.
Periostin was first called osteoblast-specific factor-2 (OSF-2) and was isolated and identified as a gene specifically expressed in the mouse osteoblast cell line MC3T3-E1 (JPA No. HEI-5-268982, Takeshita S. et al., Biochem J (1993) 294, 271-8), and later came to be known as periostin and was reported to have adhesion-promoting activity in osteoblast cells (Horiuchi K. et al., J. Bone Miner. Res. (1999) 14, 1239-49).
In early studies, periostin was thought to be an extracellular matrix specifically expressed in bone tissue. However, it is currently known to be expressed not only in bone tissue but also very highly at the onset of heart failure (Katsuragi N. et al., Circulation (2004) 110, 1806-13, Wang D. et al., Hypertension (2003) 42, 88-95), aneurysms (Peters D G. et al., Stroke (2001) 32, 1036-42), highly metastatic cancers (Shao R. et al., Mol Cell Biol. (2004) 24, 3992-4003, Gonzalez H E. et al., Arch Otolaryngol Head Neck Surg. (2003) 129, 754-9, Sasaki H. et al., Breast Cancer Res Treat. (2003) 77, 245-52), preeclampsia (Sasaki H. et al., Am J Obstet. Gynecol. (2002) 186, 103-8) as well as very slightly in normal tissue. Moreover, some periostin splice variants were shown to be expressed in osteoblasts (Takeshita S. et al., Biochem J (1993) 294, 271-8, Horiuchi K. et al., J. Bone Miner. Res. (1999) 14, 1239-49, Litvin J. et al., J Cell Biochem. (2004) 92, 1044-61, Katsuragi N. et al., Circulation (2004) 110, 1806-13).
As to functions of periostin, a periostin splice variant consisting of 811 amino acids (corresponding to PN-2 in FIG. 1) (Horiuchi K. et al., J. Bone Miner. Res. (1999) 14, 1239-49) and a periostin splice variant consisting of 782 amino acids (Gillan L, et al., Cancer Res. (2002) 62, 5358-64) were reported to have cell adhesive properties. In contrast, it has been reported that a periostin splice variant consisting of 838 amino acids (corresponding to PN-1 in FIG. 1) prevents heart fibroblasts from adhering to a plate coated with the periostin splicing variant, i.e., has no cell adhesive activity; the gene expression of the periostin splice variant consisting of 838 amino acids (corresponding to PN-1 in FIG. 1) is significantly increased in heart failure model rats as compared with normal rats; this variant is an aggravating factor inducing heart dilation; and that the survival rate was significantly increased by inhibition of the expression of this protein (Katsuragi N. et al., Circulation (2004) 110, 1806-13). Further, there is a report of a prophylactic or therapeutic agent for heart failure, in which an antisense nucleotide against the periostin splice variant consisting of 838 amino acids is used to suppress expression of the periostin splicing variant (Republication WO02/020055).
In addition, the inventors of the present invention have reported a prophylactic or therapeutic agent for heart failure, which is based on the following findings: the periostin splice variant consisting of 811 amino acids (corresponding to PN-2 in FIG. 1) is involved in cell adhesion whereas the periostin splice variant consisting of 838 amino acids (corresponding to PN-1 in FIG. 1) has cell detachment activity; an antibody against an antigen composed of the Exon-17 sequence inhibits the cell detachment activity; and improved heart function was observed in acute myocardial infarction model animals (Japanese Patent Application No. 2005-380009).
As to cancers, various reports have been issued on high level expression of periostin in highly metastatic cancers [Erkan M. et al. Gastroenterology, 132(4), 1447-64 (2007) (pancreatic cancer), Siriwardena B S. et al. Br J Cancer, 95(10), 1396-403 (2006) (oral cancer), Baril P. et al. Oncogene, 26(14), 2082-94 (2007) (pancreatic cancer), Grigoriadis A. et al. Breast Cancer Res, 8(5), R56 (2006) (breast cancer), Kudo Y. et al. Cancer Res, 66(14), 6928-35 (2006) (head and neck cancer), Bao S. et al. Cancer Cell. 5(4), 329-39 (2004) (colon cancer), Shao R. et al., Mol Cell Biol. (2004) 24, 3992-4003 (breast cancer), Sasaki H. et al., Breast Cancer Res Treat. (2003) 77, 245-52 (breast cancer), Sasaki H. et al. Cancer Lett., 72(1), 37-42 (2001) (thymic cancer), Sasaki H. et al. Cancer, 92(4), 843-8 (2001) (non-small cell lung cancer), Gonzalez H E. et al., Arch Otolaryngol Head Neck Surg. (2003) 129, 754-9 (head and neck squamous cell carcinoma)]. Also, highly metastatic cancers are reported to express the transcription factor Twist at high level (Thiery J P. et al. Nat. Med. 10(8), 777-8 (2004), Yang J, et al. Cell. 117(7), 927-39 (2004)) and receive attention, but there is a report showing that Twist is also located in the promoter region of periostin (Oshima A, et al. J Cell Biochem, 86(4), 792-804 (2002)). In addition, it has been reported that the human fetal kidney epithelial cell line 293T, which is carcinogenic and non-metastatic, enhances its invasion ability when introduced with the periostin gene (Yan W. et al. J Biol. Chem., 281(28), 19700-8 (2006))). It has also been reported that a rat homolog of mouse periostin was less expressed in various cancer cells, introduction of the periostin gene into bladder cancer cells inhibited invasion of the bladder cancer cells, and introduction of the periostin gene into mouse melanoma B16-F10 cells inhibited their metastasis to lung (Kim C J, et al. Int J Cancer, 117(1), 51-8 (2005)).
As shown above, it has been suggested that expression of the periostin gene is related to the pathology of heart failure, but the relationship between the structure of periostin splicing variants and heart failure has been unknown.
Also, it has been suggested that expression of the periostin gene is related not only to the pathology of heart failure, but also to the pathology of cancer. However, it is unknown what function each splice variant has on the progress of cancer condition.
Thus, we made an attempt to clarify the structure of periostin related to the pathology of heart failure by using antibodies.
As to periostin antibodies, there are reports of an antibody related to the inhibition of chemotaxis of periostin (Lindner V. et al., Arterioscler Thromb Vasc Biol. (2005) 25, 77-83) and an antibody having inhibitory activity against periostin-induced cell growth (Tai I T, et al., Carcinogenesis (2005) 26, 908-15). However, there has been neither a report of antibodies showing the structure of a region responsible for cell adhesive activity of periostin nor a report showing the relation between the cell adhesive activity of periostin and diseases such as heart failure.
As to antibodies against periostin, there are reports of an anti-periostin antibody which inhibits periostin overexpression-enhanced migration of mesenchymal cells (Lindner V. et al., Arterioscler Thromb Vasc Biol. (2005) 25, 77-83) and an anti-periostin antibody which inhibits periostin-induced growth and cell differentiation in colorectal cancer (Tai I T. et al., Carcinogenesis (2005) 26, 908-15).